This invention comprises an improved, more economical process for synthesis of BMY 21502 which is suitable for adaption to large-scale manufacture. BMY 21502 is chemically 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2-pyrrolid inone and its synthesis and that of related compounds has been disclosed by Mattson, et al. in U.S. Pat. No. 4,826,843 issued May 2, 1989. BMY 21502 is a promising pharmaceutical agent which enhances cerebral functioning, improves memory and learning, and reverses amnesias. Currently BMY 21502 is undergoing clinical trials designed to confirm its safety and efficacy as an ethical pharmaceutical.
The demand for drug substance has increased substantially with the advent of clinical testing and future need for much larger amounts is projected due to the intended commercialization of BMY 21502. The prior art process for preparation of BMY 21052 (Scheme A) proved to be unsatisfactory for adaptation to the larger scale processing required to meet these demands for large quantities of the drug. ##STR1##
The laboratory scale process disclosed in U.S. Pat. No. 4,826,843 did not include step 3 of Scheme A because commercially available 4-chloro-2-trifluoromethylpyrimidine was employed. This intermediate can also be synthesized by readily available literature methods, e.g., J. Org. Chem. 26/4504 (1961). Various halopyrimidines can be obtained commercially in laboratory quantities. It is appreciated by those familiar with chemical process scale-up that price considerations and lack of availability of bulk quantities of required chemical intermediates generally require synthesis of these intermediates for larger scale processes.
It is further appreciated by those skilled in process development that many processes, procedures, and/or reactions are not amenable to being carried out on a large scale as is done in a pilot plant or a manufacturing facility. Some examples of situations where scale-up can be problematic may involve the use of hazardous or toxic reagents and/or solvents; highly exothermic reactions; high pressure or high vacuum processes, such as those required for certain high pressure reactions or high vacuum distillations; chromatographic separation and/or purification; reduced yield on scale-up and the like. A more recent consideration for large scale operations is the limitations which have been set on certain emissions as well as the disposal of waste products from chemical processing. Processes involving these elements incur higher levels of cost in production.
The prior art process for preparation of BMY 21502 is not amenable to scale-up for many of the reasons listed above as well as other process problems unique to the actual reactions employed.
Preparation of the 2-pyrrolidinone anion (in Step 1) is accompanied by evolution of hydrogen gas. In this particular instance a large formation of a stable foam also occurs and its presence causes the stoppage of further addition of 2-pyrrolidinone in order to prevent spillover of the reactants.
Reduction of the pyridine intermediate IV in Step 2 does not proceed very well on a larger scale if IV is not purified by vacuum distillation prior to its reduction.
In Step 3 the major problem concerns bulk preparation of the starting 4-hydroxy-2-trifluoromethylpyrimidine, XVI. Prior synthesis of this chemical intermediate is necessary to provide the quantities required for large-scale production. The available synthetic routes to XVI all employ either trifluoroacetonitrile (CF.sub.3 CN; an expensive noxious gas) or its derivative, trifluoroacetamidine (CF.sub.3 C(NH)NH.sub.2 ; also expensive, noxious, and with limited stability) as the synthetic source for the trifluoromethyl moiety in XVI.
Finally in Step 4, purification of the target product, BMY 21502, requires chromatographic purification, an important limiting factor for scale-up.
An objective then of the present invention is to provide a chemical process which can be operated on a large scale. A second objective is to provide a chemical process whose cost considerations allow its utilization on a large scale to be economical.